Reducing the Abuse and Diversion of Prescription Opioids: The U.S. Experience with Abuse-deterrent Formulations

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on November 16, 2015

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Trends of Abuse and Diversion of Prescription Drugs in the United States

A noticeable increase in diversion and abuse of prescription opioids started in the mid-1980s and has ­progressively worsened for the past 25 years, with ­opioids ranking higher among the causes of accidental death than historical norms.1 Beginning in 2010, rates of abuse for prescription opioid analgesics unexpectedly flattened; but rates of heroin abuse began to increase.2 Deaths involving prescription opioids increased until 2011 and then plateaued; however, they are still high, with 16,235 deaths in the United States in 2013 implicating opioids as one—or the—cause of death.1
There are many causes for the epidemic in opioid analgesic deaths, and many solutions will be needed to reverse it. Potential solutions include: enhanced law enforcement; improved education of prescribers, caregivers and patients; regular use of prescription monitoring plans; adherence to prescribing guidelines; proper drug disposal (e.g., drug take-back days); and “take-home” naloxone. Perhaps the most controversial concept, however, is abuse-deterrent formulations (ADFs), which in Canada are termed tamper-resistant formulations (TRFs).
TRFs have been criticized by some parties as a ­gimmick proposed by the pharmaceutical industry to increase profits. However, the rationale behind abuse deterrence—as well as the subsequent dramatic decrease in abuse of these products—suggests that they can have an important effect on drug abuse. As the technology improves, we can expect even bigger effects. The Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System performs nationwide surveillance of prescription drug abuse throughout the United States.2 Given that RADARS collects data that identifies the specific ­opioid analgesic involved (e.g., can distinguish branded products from generic products of the same drug class), it offers a unique perspective on the abuse of TRFs.

The Rationale Behind TRFs

The first TRF was introduced in the United States in 2010, when a controlled-release formulation of oxycodone (OxyContin®) was replaced with an innovative difficult-to-crush version.3 In 2012, that new product became available in Canada under the trade name OxyNEO®.4 The original OxyContin was easy to abuse by simply crushing a tablet between two spoons and snorting or solubilizing the resulting powder for injection. The effect of the new product has been ­dramatic: diversion and abuse of oxycodone decreased immediately, and the effect has been maintained for at least four years (Figure 1).5

Why was a TRF of oxycodone effective? In general, there are two groups of abusers, and a difficult-to-crush formulation can interfere with abuse by both groups. The first group involves people who start as patients with a legitimate medical need for opioid analgesics—people in pain who seek healthcare to treat their pain. Although it was once widely taught in medicine that appropriate prescribing of an opioid rarely leads to abuse or addiction, we now know this is not always true. When used in patients to treat pain, a small proportion of individuals will ­develop abuse behaviours, and some will become ­addicted.6 The true value of TRFs lie in their ability to help the large group of patients who are exposed to ­prescription opioids each year for treatment of pain (Figure 2).5 The first step down the path to addiction for individuals in pain often lies in chewing or crushing their medication. Early on, they are not addicted and are unlikely to be motivated to overcome the TRF mechanism. For individuals in pain who are simply trying to get relief, but have a susceptibility to abuse/addiction, a TRF can impede their progress toward addiction.

The second group of abusers involves people who abuse other drugs and decide to expand into opioids. Prescription opioids are easy to access and are perceived as being safer than heroin. One should keep in mind that there is some mixing of these two groups. For example, an individual could be seeking legitimate pain relief, but also have a history of drug abuse. Indeed, research shows that these people are at higher risk of opioid abuse.7 Often, the concept of TRFs is criticized for not completely preventing abuse by established “hard-core” abusers and addicts.8 The assumption is that a difficult-to-crush formulation is meant to prevent established abusers from snorting or injecting their drugs. It is fascinating to note that a small portion of abusers indicate that they stopped using the high-risk routes of intravenous or intranasal abuse, and a few even reduced or ended their substance abuse in response to the introduction of reformulated controlled-release oxycodone.9 With other drugs being readily available, however, it is more likely that abusers will switch to another opioid.9 All patients chronically treated with prescription opioids should be monitored to ensure that they are personally using their analgesic (rather than selling it) and that they are not abusing other drugs.
Interestingly, our results from the RADARS System indicate that abuse of oxycodone via oral and non-oral routes has decreased since its reformulation.9 These results seem to contradict the theory behind TRFs: it has always been assumed that abuse via the oral route could not be deterred because abusers could simply take more intact tablets. So, why would oral abuse decrease? The most likely reason is that many abusers chew or crush their drug before they swallow it, a phenomenon not widely understood. Thus, a difficult-to-crush formulation would be expected to deter some oral abuse, but more non-oral abuse, which is precisely what research results show.10
The other main criticism of TRFs is that they simply push abusers to other opioids, and those alternatives include heroin.9 This is true, as an addicted individual will switch to almost any other available opioid to fulfill their need. Unfortunately, the current crushable formulations of various opioids are abused at astonishing rates. To leave them available on the market simply fuels the epidemic.

Conclusions

Several solutions will be needed to stem the tide of opioid abuse. Like most large public health challenges, it is likely to require many different interventions to make a large difference; and a large difference is needed. In 2013, more than 16,000 people died in the United States from overdose of opioids, often in combination with other drugs.11 To address the issue of abuse and addiction, expansion of substance abuse treatment programs is essential. In addition, greater awareness is needed among patients, the general public and prescribers of opioids analgesics. TRFs offer one strategy to reduce abuse. As more TRF products become available, they will become more effective at stemming overall abuse.

Clinical Commentary: A Canadian Perspective

While we see that there is an increasing amount of data to ­support tamper-resistant formulations (TRFs) as a deterrent against drug abuse, misuse and diversion, it remains critical to screen and monitor all patients being prescribed opioids. Pre-screening all patients prior to initiating prescription opioids with respect to their abuse risks (e.g., Opioid Risk Tool for family and personal history of alcohol, illicit and prescription drug abuse, and mental health history) and screening for illicit drugs in a urine drug screen are becoming standards of care in Canada. A patient with alcohol or illicit drugs in his/her urine test during a regularly scheduled medical appointment should raise a red flag of concern, and a pain and/or addiction specialist should be consulted prior to initiating any opioids or controlled medications.
Although urine drug testing is important, it is often confusing to physicians, as urine drug-screen reports are qualitative and not quantitative. A negative drug screen in a patient being prescribed opioids may be wrongly reported a “negative,” in that the amount detected in the urine is below the threshold for ­calling it a “positive” test. Additionally, synthetic and semi-­synthetic opioids may not always be picked up on all urine drug screens, adding to the risk of wrongly accusing a patient of not taking (and possibly diverting) his/her prescribed opioids.
A narcotic agreement signed by the patient and his/her physician sets up rules and guidelines around a healthy respect and mutual understanding of prescription opioids, and around medication discontinuation when a patient’s pain, activities of daily living and functionality may not be improving or in the case where a patient is not taking his/her opioids as prescribed.
With increasing concerns over prescription drug abuse, ­misuse and diversion, Canadian policymakers, regulatory agencies, medical and healthcare professionals, and the pharmaceutical industry can draw from the American experience. The data collected by the RADARS System should give reassurance to Canadian healthcare regulators and clinicians that TRFs of opioids are safer and do mitigate abuse and diversion potential, as it shows trends towards TRFs being used as intended and deterring misuse.5 Strategies including drug manufacturing (developing TRFs), public education, and physician education and collaboration with other healthcare professionals (e.g., pharmacists) are critical to mitigating the risks of abuse while ensuring that legitimate chronic pain patients continue to receive a high level of care. When providing optimal pain management treatment, clinicians should consider both no n-opioid and opioid medications (where necessary and appropriate) for the individual patient.

Development of this article was funded by Purdue Pharma (Canada).
The authors had complete editorial independence in the development of
this article and are responsible for its accuracy and completeness.

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